Pragma Bioscience(Habibah)

8/11/2019 Pragma Bioscience(Habibah)

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Introduction

Drug discovery take years todecade for discovering a new drugand very costly

Effortto cut down the researchtimeline and cost by reducing wet-lab experimentuse computermodelling.
http://images.google.com/imgres?imgurl=notes.cc.sunysb.edu/CAS/chemistry.nsf/pages/images1/%24File/fabi.jpg&imgrefurl=http://notes.cc.sunysb.edu/CAS/chemistry.nsf/pages/Tonge_Group&h=270&w=252&prev=/images%3Fq%3Ddrug%2Bdesign%26start%3D160%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26sa%3DNhttp://images.google.com/imgres?imgurl=notes.cc.sunysb.edu/CAS/chemistry.nsf/pages/images1/%24File/fabi.jpg&imgrefurl=http://notes.cc.sunysb.edu/CAS/chemistry.nsf/pages/Tonge_Group&h=270&w=252&prev=/images%3Fq%3Ddrug%2Bdesign%26start%3D160%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26sa%3DNhttp://images.google.com/imgres?imgurl=www.gmd.de/SCAI/europort-d/pics3/drug2.gif&imgrefurl=http://www.gmd.de/SCAI/europort-d/drug-design1.html&h=198&w=200&prev=/images%3Fq%3Ddrug%2Bdesign%26start%3D40%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26sa%3DN


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TRADITIONAL DRUG DESIGN

Lead generation:

Natural ligand / Screening

Biological Testing

Synthesis of New Compounds

Drug Design Cycle

If promising

Pre-Clinical Studies


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Structure-based Drug Design (SBDD)

Molecular Biology & Protein Chemistry

3D Structure Determination of Target

and Target-Ligand Complex

Modelling

Structure Analysisand Compound Design

Biological Testing

Synthesis of New Compounds

If promising

Pre-Clinical

Studies

Drug Design Cycle

Natural ligand / Screening


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SBDD: drug targets (usually proteins)

binding of ligands to the target (docking)

rational drug design

(benefits = saved time and $$$)


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Ligand database Target Protein

Molecular docking

Ligand docked into proteins active site
http://images.google.com/imgres?imgurl=abagyan.scripps.edu/lab/web/man/g_dock2.gif&imgrefurl=http://abagyan.scripps.edu/lab/web/man/gallery.htm&h=202&w=205&prev=/images%3Fq%3Dprotein-ligand%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8http://images.google.com/imgres?imgurl=webexhibits.org/causesofcolor/i/sects/7/protein.gif&imgrefurl=http://webexhibits.org/causesofcolor/7.html&h=188&w=179&prev=/images%3Fq%3Dprotein%26start%3D80%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8%26sa%3DNhttp://images.google.com/imgres?imgurl=www.molsoft.com/images/ligand.gif&imgrefurl=http://www.molsoft.com/icmpages/icmlite.htm&h=656&w=700&prev=/images%3Fq%3Dligand%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8http://images.google.com/imgres?imgurl=www.molsoft.com/images/ligand.gif&imgrefurl=http://www.molsoft.com/icmpages/icmlite.htm&h=656&w=700&prev=/images%3Fq%3Dligand%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8http://images.google.com/imgres?imgurl=www.molsoft.com/images/ligand.gif&imgrefurl=http://www.molsoft.com/icmpages/icmlite.htm&h=656&w=700&prev=/images%3Fq%3Dligand%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8http://images.google.com/imgres?imgurl=www.molsoft.com/images/ligand.gif&imgrefurl=http://www.molsoft.com/icmpages/icmlite.htm&h=656&w=700&prev=/images%3Fq%3Dligand%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8


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Molecular Docking of Isoniazid (INH)

and its derivatives on M. Tb. enzymes

One third of the world population is infected.

Multi-drug resistant especially in HIV/AIDS patients

As much as 30% on INH (front-line drug) resistantstrain

INH mechanism of action:* activated by KatG and binds with NAD to form INADH

* INADH inhibit InhA (protein involved in mycolic acids

synthesis)


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TUBERCOLOSIS

In SBDD needs to understand binding interaction betweenantimicrobial and its target at molecular or atomic level

X-ray crystallography and NMR are expensive and not manyprotein easily crystallized

Molecular modeling:

* the ways to mimic the behavior of molecules and molecular

systems* understand the mechanism of interaction between protein andligand at atomic level


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SBDD on the Grid

Molecular Docking Autodock 3.05

Visualization Rasmol
http://images.google.com/imgres?imgurl=www.accelrys.com/training/lifesci/wrkshp/images/ydt.jpg&imgrefurl=http://www.accelrys.com/training/lifesci/wrkshp/sbdd_i2.html&h=254&w=367&prev=/images%3Fq%3DinsightII%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8http://images.google.com/imgres?imgurl=malice.cineca.it/images/protein.jpg&imgrefurl=http://malice.cineca.it/intro.html&h=360&w=477&prev=/images%3Fq%3DinsightII%26svnum%3D10%26hl%3Den%26lr%3D%26ie%3DUTF-8%26oe%3DUTF-8


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Grid Computing

It is not a new hardware technologyrely onexisting networks

Based on Grid Middlewarefor example: Globus

Grid middleware functions: single sign-on authentication

resource discovery

resource allocation & process creation

automatic data access & transfer

transparency


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Molecular Docking on e-Science Grid

Current project, we are incorporating the molecular dockingapplication in the grid computing environment.

Why?

Docking is most popular method applied amongstMalaysian biologist.

Cheaper?
http://cgat.ukm.my/tools/admin/about_hardware.htmlhttp://cgat.ukm.my/tools/admin/about_hardware.htmlhttp://cgat.ukm.my/tools/admin/about_hardware.htmlhttp://cgat.ukm.my/tools/admin/about_hardware.html


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Automated

Docking System

Data

Management

Data

Management

PDB

Data-

base

www.pdb.orgonly if the file doesntexist in the system.

Scheduler

User

Input Parameter

(ligand, etc)

Result

Docking job

Job Status

Request File

Return File

Get File

Return

File

Return

File

GetFile

QueryPDB PDBFile

Overall Flow of Automated Docking System
http://www.pdb.org/http://www.pdb.org/


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Get InputCreate job

specification

Jobspecification

Submit Job Data

Management

Read

parameter Parameter

needed

Read macroReturn macro

Macro file

Create job file

Scheduler Job StatusMonitoring

Return status

Get status

Creating Output &

Image

Mailing

User

If job

finished

Automated Docking System: The steps in Automated Docking


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Molecular Docking Introduction Page


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Input Page


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Input Page (cont..)


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Submitting Job


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Results


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Benchmarking.

Testing on 3 SGI machines

Testing on 3 Linux Machines Pentium IV 1.70 GHz , 256 MB Memory Pentium III 1000 MHz , 512 MB Memory

Data / Molecules:

Macromolecule of wild and mutant type 14 types of ligands

Total number of docking = 14 x 2 = 28


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Testing Method (on SGI)

SGI Machine

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Script File

SGI Machine

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Script File

SGI Machine

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Script File
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Testing Method (on Linux)

1

2

1 2

1

2

2

1

globus-job-status

globus-job-submit
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Estimated free energy of binding

-25.00

-20.00

-15.00

-10.00

-5.00

0.00

INH1

INH5

INH6

INH7

INH8

INH9

INH10

INH11

INH12

INH13

INH14

INH15

INH16

INADH

Ligand

Freeenergy(kcal/mol)

ZID ENZ

Result


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Result


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Result (total time)

On SGI On Linux PC

220h 24min 59.34s 333 hrs 1 min 22 s

(1 machine= 73h 8min 21.11s) (1 machine= 111h 0min 27s)


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Result ($/time)

On SGI On Linux PC

$1.85/min $0.075/min

(1 machine= ~USD25K) (1 machine= ~USD 1.5K)


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Future Works

PRAGMA Global Storage?

Improvement of the submitting the same job. Meaning that

user can still submit the same job anytime and the system willbe able to execute it.

Create a system that will inform the user once the users job

has been finished (mailing system).

Improve the visualization of the result given once the docking

job has finished. Performance Evaluation, by doing comparison between

sequential and distributed version in the grid environment.


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Acknowledgement

Erwin Tontanso

Choong Yee Siew Dr. Fazilah Haron

Dr. Chan Huah Yong

Documents

Pragma Bioscience(Habibah)